Exosomes in viral infection:Effects for pathogenesis and treatment strategies

Exosomes are small vesicles that carry molecules from one cell to another.They have many features that make them interesting for research,such as their stability,low immunogenicity,size of the nanoscale,toxicity,and selective delivery.Exosomes can also interact with viruses in diverse ways.Emerging research highlights the significant role of exosomes in viral infections,particularly in the context of diseases like COVID-19,HIV,HBV and HCV.Understanding the intricate interplay between exosomes and the human immune system holds great promise for the development of effective antiviral therapies.An important aspect is gaining clarity on how exosomes influence the immune system and enhance viral infectivity through their inherent characteristics.By leveraging the innate properties of exosomes,viruses exploit the machinery involved in exosome biogenesis to set replication,facilitate the spread of infection,and eliminate immune responses.They can either help or hinder viral infection by modulating the immune system.This review summarizes the recent findings on how exosomes mediate viral infection and how they can be used for diagnosis or therapy.This could lead to new clinical applications of exosomes in disease management.

RECQL4 regulates DNA damage response and redox homeostasis in esophageal cancer

Objective:RECQL4(a member of the RECQ helicase family)upregulation has been reported to be associated with tumor progression in several malignancies.However,whether RECQL4 sustains esophageal squamous cell carcinoma(ESCC)has not been elucidated.In this study,we determined the functional role for RECQL4 in ESCC progression.Methods:RECQL4 expression in clinical samples of ESCC was examined by immunohistochemistry.Cell proliferation,cellular senescence,the epithelial-mesenchymal transition(EMT),DNA damage,and reactive oxygen species in ESCC cell lines with RECQL4 depletion or overexpression were analyzed.The levels of proteins involved in the DNA damage response(DDR),cell cycle progression,survival,and the EMT were determined by Western blot analyses.Results:RECQL4 was highly expressed in tumor tissues when compared to adjacent non-tumor tissues in ESCC(P<0.001)and positively correlated with poor differentiation(P=0.011),enhanced invasion(P=0.033),and metastasis(P=0.048).RECQL4 was positively associated with proliferation and migration in ESCC cells.Depletion of RECQL4 also inhibited growth of tumor xenografts in vivo.RECQL4 depletion induced G0/G1 phase arrest and cellular senescence.Importantly,the levels of DNA damage and reactive oxygen species were increased when RECQL4 was depleted.DDR,as measured by the activation of ATM,ATR,CHK1,and CHK2,was impaired.RECQL4 was also shown to promote the activation of AKT,ERK,and NF-k B in ESCC cells.Conclusions:The results indicated that RECQL4 was highly expressed in ESCC and played critical roles in the regulation of DDR,redox homeostasis,and cell survival.

Frontiers in antibiotic alternatives for Clostridioides difficile infection

Clostridioides difficile(C.difficile)is a gram-positive,anaerobic spore-forming bacterium and a major cause of antibiotic-associated diarrhea.Humans are naturally resistant to C.difficile infection(CDI)owing to the protection provided by healthy gut microbiota.When the gut microbiota is disturbed,C.difficile can colonize,produce toxins,and manifest clinical symptoms,ranging from asymptomatic diarrhea and colitis to death.Despite the steady-if not risingprevalence of CDI,it will certainly become more problematic in a world of antibiotic overuse and the post-antibiotic era.C.difficile is naturally resistant to most of the currently used antibiotics as it uses multiple resistance mechanisms.Therefore,current CDI treatment regimens are extremely limited to only a few antibiotics,which include vancomycin,fidaxomicin,and metronidazole.Therefore,one of the main challenges experienced by the scientific community is the development of alternative approaches to control and treat CDI.In this Frontier article,we collectively summarize recent advances in alternative treatment approaches for CDI.Over the past few years,several studies have reported on natural product-derived compounds,drug repurposing,highthroughput library screening,phage therapy,and fecal microbiota transplantation.We also include an update on vaccine development,pre-and probiotics for CDI,and toxin antidote approaches.These measures tackle CDI at every stage of disease pathology via multiple mechanisms.We also discuss the gaps and concerns in these developments.The next epidemic of CDI is not a matter of if but a matter of when.Therefore,being well-equipped with a collection of alternative therapeutics is necessary and should be prioritized.

Cullin 4B-RING E3 ligase complex in immune cell differentiation and function

CUL4B,which encodes the scaffold protein in the CRL4B complex,is a commonly mutated gene in X-linked intellectual disability[10,11].In addition to intellectual disability,patients with CUL4B mutations present with an elevated number of monocytes in peripheral blood[10],implying a role for CUL4B in regulating monocytes/macrophages.Monocytes/macrophages are critical players in innate immunity.Hung et al.found that depletion of CUL4B in myeloid cells aggravated lipopolysaccharide(LPS)-induced acute peritonitis[3].They further showed that after LPS stimulation,Cul4b-deficient macrophages secreted more chemokines than control macrophages,which might have accounted for the elevated infiltration of immune cells into the peritoneum[3].Our previous work demonstrated that myeloid-specific Cul4b-knockout mice exhibited reduced survival after LPS injection or Salmonella typhimurium infection compared to control mice[6].In contrast to work from Hung et al.,which showed that Cul4b-deficient macrophages secreted less TNFαand IL-6 after LPS stimulation[3],our works showed that deletion of CUL4B in macrophages increased the production of proinflammatory cytokines and decreased the expression of the anti-inflammatory cytokine IL-10 in response to the activation of Toll-like receptor(TLR).CUL4B regulation of macrophages relies on the ubiquitination activity of the CRL4B complex.The CRL4B complex catalyzes monoubiquitination of H2AK119 at the promoter of Pten,resulting in the repression of Pten transcription and subsequent activation of AKT and AKT-dependent inhibition of GSK3β,which suppresses TLR-triggered proinflammatory responses(Fig.1B)[6].

Competing Risks Data Analysis with High-dimensional Covariates:An Application in Bladder Cancer

Analysis of microarray data is associated with the methodological problems of high dimension and small sample size. Various methods have been used for variable selection in high- dimension and small sample size cases with a single survival endpoint. However, little effort has been directed toward addressing competing risks where there is more than one failure risks. This study compared three typical variable selection techniques including Lasso, elastic net, and likelihood-based boosting for high-dimensional time-to-event data with competing risks. The per- formance of these methods was evaluated via a simulation study by analyzing a real dataset related to bladder cancer patients using time-dependent receiver operator characteristic （ROC） curve and bootstrap .632 ＋ prediction error curves. The elastic net penalization method was shown to outper- form Lasso and boosting. Based on the elastic net, 33 genes out of 1381 genes related to bladder cancer were selected. By fitting to the Fine and Gray model, eight genes were highly significant（P 〈 0.001）. Among them, expression of RTN4, SON, IGF1R, SNRPE, PTGR1, PLEK, and ETFDHwas associated with a decrease in survival time, whereas SMARCAD1 expression was asso- ciated with an increase in survival time. This study indicates that the elastic net has a higher capacity than the Lasso and boosting ＇for the prediction of survival time in bladder cancer patients. Moreover, genes selected by all methods improved the predictive power of the model based on only clinical variables, indicating the value of information contained in the mieroarray features.